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We conducted a large-scale in vivo Drosophila screen to discover novel mechanosensitive, inflammatory genes. From this screening, we identified smarcd3, psmd12 (mouse ortholog of RPN5), and IRE1 as novel regulators of NFκB in inflammatory response. Of these, smarcd3 acts as an anti-inflammatory repressor of NFκB in endothelial cells, which might play an important role in regulating endothelial inflammation in a shear-responsive manner.